The invention relates to the chemical modification of cellulosic dialysis membranes to improve their biocompatibility.
West German Patent 2,705,735 discloses a dialysis membrane for hemodialysis with antithrombogenic compounds chemically bonded thereto, the dialysis membrane consisting of two or more layers of a cellulose regenerated from cuprammonium solutions. This cellulose was obtained from separately fed holes in a spinneret and contains the antithrombogenic-active substances in chemically bonded form.
Laid-open West German Patent Application 2,748,858 of 31 Oct., 1977 describes the preparation of antithrombogenic polymer materials prepared by the following process:
Reaction of reactive polymers with synthetic fibrinolytic compounds (covalent bonding)
Treatment of polymers containing anion-exchange groups with a synthetic fibrinolytic compound (ionic bonding);
Treatment of polymer materials with solutions of synthetic fibrinolytic compounds (adsorption).
Such a membrane modification is ruled out, since biocompatibility-improving compounds that are bonded only adsorptively to the polymer can pass into the bloodstream during dialysis.
U.S. Pat. No. 3,475,410 of 28 Oct. 1969 and the publication in Vol. XII Trans. Amer. Soc. Artif. Int. Organs, 1966, pp. 139-150 describe antithrombogenic cellulose membranes that are obtained by treatment of the cellulose, first with ethyleneimine, then with heparin. According to our studies, however, membranes modified with ethylamino groups have lower biocompatibility than unmodified membranes.
Japanese Applications 57-162,701 and 57-162,702 also claim antithrombogenic cellulose membranes. These are prepared by grafting vinyl monomers onto cellulose or cellulose derivatives, followed by heparinization. In addition to the grafting reaction, however, a homopolymerization is also to occur. Although no permanent bond exists between the homopolymerized product and cellulose, the former cannot be completely removed from the membrane despite intensive washing. Therefore, small amounts of the heparinized product can always pass into the bloodstream during blood dialysis.
Japanese Kokai 60-203,265 describes high molecular weight cellulose products for making medical instruments with anticoagulant properties. It involves mixtures of polycationic and polyanionic cellulose derivatives, which are normally obtained by intermixing appropriate polymer solutions. Such water-insoluble salts are unsuitable as membrane materials, since the danger always exists that they will be converted by double decomposition effects into a compound that is water-soluble or strongly swellable in water.
However, it has already been proposed in West German Laid-open Application 1,720,087 to reduce the risk of blood coagulation by reacting the polymer material of the membrane with an alkyl halide and thereafter reacting the resulting material with an alkali metal salt of an antithrombogenic material with cationic residue (e.g., heparin or a heparinoid compound), whereby the possible alkyl halides may also include haloalkyldialkylamines. Cellulose and cellulose acetate are among the possible polymers.
An antithrombogenic effect of these dialysis membranes is observed only if the degree of substitution of the modified cellulose is high, i.e., higher than at least 0.1, and when a preheparinization with relatively high heparin concentration (solutions with 0.1 to 1 weight percent) is performed in a separate step.
West German Laid-open Application 3,341,113 discloses a dialysis membrane in the form of flat films, tubular films or hollow filaments consisting of regenerated cellulose, wherein polymeric acids are chemically bonded at least to one membrane surface by means of bridge-forming agents chemically bonded to the cellulose. Aside from the fact that the production is relatively expensive, even though it is performed in a posttreatment, the effectiveness is substantially limited to a reduction of leukopenia. Because of the large molecules of the polymeric acids, bonding by means of the bridge-forming agents occurs only at the surface of the membrane.
Furthermore, West German Laid-open Application 3,438,531 discloses a dialysis membrane wherein isocyanate prepolymers are bonded to the cellulose. The effectiveness is limited in a manner similar to that described hereinabove to celulose membranes modified with polymeric acids.
A dialysis membrane with improved biocompatibility has become known from West German Laid-open Application 3,524,596, which is characterized by the fact that the mean degree of substitution of a modified cellulose is equal to 0.02 to 0.07. Suitable celluloses modified by substitution are esterified or etherified celluloses. Preferably, the dialysis membrane from cellulose contains such modified cellulose that has a structure represented by the formula EQU Cellulose-R'--X--Y
wherein
X stands for --NR"-- and/or --N+R".sub.2 and/or --S-- and/or --SO-- and/or --SO.sub.2 -- and/or --CO--NR-- and/or --CO--O-- and/or --O--; PA1 Y stands for --R and/or --NR.sub.2 and/or --Si(OR").sub.3 and/or --SO.sub.3 H and/or --COOH and/or --PO.sub.3 H.sub.2 and/or --N+HR.sub.2 or salts thereof; PA1 R' stands for an alkylene group and/or cyclo alkylene group and/or arylene group with a total of 1 to 25C atoms; PA1 R" stands for a hydrogen atom or R, and PA1 R stands for an alkyl group with 1 to 5C atoms and/or a cycloalkyl group and/or aryl group.
This dialysis membrane was already capable of reducing blood coagulation, leukopenia and complement activation to a considerable degree. However, adsorption of beta-2-microglobulin to a noteworthy degree was not successfully achieved.
Apart from the fact that dialysis membranes from synthetic or natural polymers, when used in artificial kidneys, can very easily induce blood coagulation, which is substantially prevented by appropriate drug treatment, in the case of dialysis membranes from regenerated cellulose there is often a temporary decrease in leukocytes in the first period of dialysis treatment when a kidney patient is treated with dialyzers having cellulose membranes. This effect is caled leukopenia.
Leukopenia is a reduction in the number of leukocytes (white blood corpuscles) in the circulating blood. The number of white blood corpuscles in humans is about 4,000 to 12,000 cells/mm.sup.3.
Leukopenia associated with dialysis is most pronounced 15 to 20 min after the start and it is possible for the neutrophils (which are the leukocytes which can be stained with neutral or simultaneously with acidic and basic dyes) to disappear almost completely. Subsequently, the number of leukocytes recovers again within about one hour to almost the initial level or exceeds it.
If, after the leukocytes have recovered, a new dialyzer is connected, leukopenia will occur again to the same extent.
Cellulose membranes cause pronounced leukopenia. Even though the clinical significance of leukopenia has not been scientifically elucidated, there is nevertheless a desire for a dialysis membrane for hemodialysis which does not exhibit the leukopenic effect, without thereby deleteriously affecting the other very desired properties of dialysis membranes from regenerated cellulose.
In the case of hemodialysis using membranes from regenerated cellulose, a distinct complement activation has also been found beside the leukopenia. The complement system within the blood serum is a complex plasma-enzyme system which consists of many components and acts in various ways to prevent damage due to invading foreign cells (bacteria etc.). When antibodies against the invading organism are present, there can be complement-specific activation by the complex of the antibodies with antigenic structures of the foreign cells, otherwise complement activation takes place by an alternative pathway due to special surface features of the foreign cells. The complement system is based on a multiplicity of plasma proteins. After activation, these proteins react specifically in a specific sequence with one another and, finally, a cell-damaging complex which destroys the foreign cell is formed.
Individual components release peptides which induce inflammatory manifestations and can occasionally also have undesired pathological consequences for the organism. It is assumed that in the case of hemodialysis membrane made from regenerated cellulose the activation takes place by the alternative pathway. These complement activations are detected objectively by determining the complement fragments C.sub.3a and C.sub.5a.
In this connection, reference is made to the following studies: D. E. Chenoweth et al., Kidney International vol. 24, pages 746 ff., 1983 and D. E. Chenoweth, Asaio-Journal vol. 7, pages 44 ff., 1984.
An object of the present invention was to provide biocompatible dialysis membranes of regenerated cellulose in the form of flat films, tubular films or hollow filaments, which membranes have good biocompatibility for the lowest possible degree of substitution of modified celluloses and in which the cellulose was regenerated in the cuprammonium process. Cellulose esters and cellulose carbamates cannot be readily processed in the cuprammonium process, because, on the one hand, they are insoluble for higher degrees of substitution and, on the other, they are readily saponified in the alkaline medium of the cuprammonium solution.